Injectable scaffold for treatment of intracranial aneurysms and related technology

ABSTRACT

A method for treating an aneurysm in accordance with a particular embodiment of the present technology includes intravascularly delivering a mixture including a biopolymer (e.g., chitosan) and a chemical crosslinking agent (e.g., genipin) to an aneurysm. The method further includes mixing the biopolymer and the chemical crosslinking agent to initiate chemical crosslinking of the biopolymer. The mixture is delivered to the aneurysm via a lumen and an exit port of a catheter while the chemical crosslinking is ongoing. The mixture exits the catheter as a single cohesive strand that at least partially agglomerates to form a mass occupying at least 75% of a total internal volume of the aneurysm. During delivery of the mixture, the method includes expanding a tubular flow diverter to reinforce a neck of the aneurysm.

CROSS-REFERENCE TO RELATED APPLICATION(S)

This application is a divisional of U.S. patent application Ser. No.15/299,929, filed Oct. 21, 2016, the disclosure of which is incorporatedherein by reference in its entirety.

TECHNICAL FIELD

The present technology is related to systems, devices, and methods fortreating intracranial aneurysms.

BACKGROUND

An intracranial aneurysm is a portion of an intracranial blood vesselthat bulges outward from the blood vessel's main channel. This conditionoften occurs at a portion of a blood vessel that is abnormally weakbecause of a congenital anomaly, trauma, high blood pressure, or foranother reason. Once an intracranial aneurysm forms, there is asignificant risk that the aneurysm will eventually rupture and cause amedical emergency with a high risk of mortality due to hemorrhaging.When an unruptured intracranial aneurysm is detected or when a patientsurvives an initial rupture of an intracranial aneurysm, vascularsurgery is often indicated. One conventional type of vascular surgeryfor treating an intracranial aneurysm includes using a microcatheter todispose a platinum coil within an interior volume of the aneurysm. Overtime, the presence of the coil should induce formation of a thrombus.Ideally, the aneurysm's neck closes at the site of the thrombus and isreplaced with new endothelial tissue. Blood then bypasses the aneurysm,thereby reducing the risk of aneurysm rupture (or re-rupture) andassociated hemorrhaging. Unfortunately, long-term recanalization (i.e.,restoration of blood flow to the interior volume of the aneurysm) afterthis type of vascular surgery occurs in a number of cases, especiallyfor intracranial aneurysms with relatively wide necks and/or relativelylarge interior volumes.

Another conventional type of vascular surgery for treating anintracranial aneurysm includes deploying a flow diverter within theassociated intracranial blood vessel. The flow diverter is often a meshtube that causes blood to preferentially flow along a main channel ofthe blood vessel while blood within the aneurysm stagnates. The stagnantblood within the aneurysm should eventually form a thrombus that leadsto closure of the aneurysm's neck and to growth of new endothelialtissue, as with the platinum coil treatment. One significant drawback offlow diverters is that it may take weeks or months to form aneurysmalthrombus and significantly longer for the aneurysm neck to be coveredwith endothelial cells for full effect. This delay may be unacceptablewhen risk of aneurysm rupture (or re-rupture) is high. Moreover, flowdiverters typically require antiplatelet therapy to prevent a thrombusfrom forming within the main channel of the blood vessel at the site ofthe flow diverter. Antiplatelet therapy may be contraindicated shortlyafter an initial aneurysm rupture has occurred because risk ofre-rupture at this time is high and antiplatelet therapy tends toexacerbate intracranial hemorrhaging if re-rupture occurs. For these andother reasons, there is a need for innovation in the treatment ofintracranial aneurysms. Given the severity of this condition, innovationin this field has immediate life-saving potential.

SUMMARY

Various examples of aspects of the subject technology are described asnumbered clauses (1, 2, 3, etc.) for convenience. These are provided asexamples and do not limit the subject technology. It is noted that anyof the dependent clauses may be combined in any combination, and placedinto a respective independent clause, e.g., Clause 1, Clause 13, orClause 22.

1. A method for treating an aneurysm, the method comprising:

-   -   intravascularly advancing a catheter toward an aneurysm at a        portion of a blood vessel, wherein the catheter includes an        elongate lumen and an exit port at a distal end portion of the        lumen;    -   mixing a biopolymer and a chemical crosslinking agent to        initiate chemical crosslinking of the biopolymer;    -   flowing the biopolymer and the chemical crosslinking agent        toward an internal volume of the aneurysm via the lumen while        the chemical crosslinking is ongoing; and    -   delivering the biopolymer and the chemical crosslinking agent        from the lumen into the internal volume via the exit port while        the chemical crosslinking is ongoing.

2. The method of Clause 1 wherein the aneurysm is an intracranialaneurysm.

3. The method of Clause 1 wherein:

-   -   the biopolymer has a non-zero degree of chemical crosslinking        before being mixed with the chemical crosslinking agent; and    -   mixing the biopolymer and the chemical crosslinking agent        includes mixing the biopolymer and the chemical crosslinking        agent to increase the degree of chemical crosslinking.

4. The method of Clause 1 wherein delivering the biopolymer and thechemical crosslinking agent from the lumen into the internal volumeincludes delivering the biopolymer and the chemical crosslinking agentfrom the lumen into the internal volume as components of a singlecohesive strand that at least partially agglomerates to form a massoccupying at least 75% of the internal volume, and wherein the internalvolume is a total internal volume of the aneurysm.

5. The method of Clause 1, further comprising:

-   -   flowing a physical crosslinking agent toward the internal volume        via the lumen with the biopolymer and the chemical crosslinking        agent; and    -   delivering the physical crosslinking agent from the lumen into        the internal volume via the exit port with the biopolymer and        the chemical crosslinking agent.

6. The method of Clause 5 wherein:

-   -   the biopolymer includes chitosan, a derivative of chitosan, an        analog of chitosan, or a combination thereof;    -   the chemical crosslinking agent includes genipin, a derivative        of genipin, an analog of genipin, or a combination thereof; and    -   the physical crosslinking agent includes β-glycerophosphate, a        derivative of β-glycerophosphate, an analog of        β-glycerophosphate, or a combination thereof

7. The method of Clause 1 wherein the biopolymer includes chitosan, aderivative of chitosan, an analog of chitosan, or a combination thereof.

8. The method of Clause 7 wherein the chemical crosslinking agentincludes genipin, a derivative of genipin, an analog of genipin, or acombination thereof.

9. The method of Clause 8 wherein mixing the biopolymer and the chemicalcrosslinking agent includes mixing the biopolymer and the chemicalcrosslinking agent such that a weight ratio of the biopolymer to thechemical crosslinking agent is within a range from 10:1 to 100:1.

10. The method of Clause 1, further comprising reinforcing a neck of theaneurysm while the biopolymer and the chemical crosslinking agent aredisposed within the internal volume and while the chemical crosslinkingis ongoing.

11. The method of Clause 10, further comprising:

-   -   intravascularly advancing a balloon toward the portion of the        blood vessel while the balloon is in a low-profile state; and    -   moving the balloon from the low-profile state toward an expanded        state after advancing the balloon toward the portion of the        blood vessel,    -   wherein reinforcing the neck includes reinforcing the neck with        the balloon in the expanded state.

12. The method of Clause 10, further comprising:

-   -   intravascularly advancing a tubular flow diverter toward the        portion of the blood vessel while the flow diverter is in a        low-profile state; and    -   moving the flow diverter from the low-profile state toward an        expanded state after advancing the flow diverter toward the        portion of the blood vessel,    -   wherein reinforcing the neck includes reinforcing the neck with        the flow diverter in the expanded state.

13. A method for treating an aneurysm, the method comprising:

-   -   disposing a tissue scaffold material including biopolymer and a        chemical crosslinking agent within an internal volume of an        aneurysm at a portion of a blood vessel, wherein the tissue        scaffold material has a first storage modulus on a pascal scale        immediately after being disposed within the internal volume;    -   reinforcing a neck of the aneurysm while the tissue scaffold        material is disposed within the internal volume and while        chemical crosslinking of the biopolymer is occurring; and    -   reducing reinforcement of the neck, wherein the tissue scaffold        material has a second storage modulus on a pascal scale        immediately after reducing reinforcement of the neck, and        wherein the second storage modulus is at least 20% greater than        the first storage modulus.

14. The method of Clause 13 wherein the aneurysm is an intracranialaneurysm.

15. The method of Clause 13 wherein:

-   -   the chemical crosslinking has an endpoint at which the tissue        scaffold material has a third storage modulus on a pascal scale;        and    -   the first storage modulus is within a range from 40% to 80% of        the third storage modulus.

16. The method of Clause 13 wherein disposing the tissue scaffoldmaterial within the internal volume includes delivering the tissuescaffold material into the internal volume as a single cohesive strandthat at least partially agglomerates to form a mass occupying at least75% of the internal volume, and wherein the internal volume is a totalinternal volume of the aneurysm.

17. The method of Clause 13 wherein the tissue scaffold materialincludes a physical crosslinking agent.

18. The method of Clause 17 wherein:

-   -   the biopolymer includes chitosan, a derivative of chitosan, an        analog of chitosan, or a combination thereof;    -   the chemical crosslinking agent includes genipin, a derivative        of genipin, an analog of genipin, or a combination thereof; and    -   the physical crosslinking agent includes β-glycerophosphate, a        derivative of β-glycerophosphate, an analog of        β-glycerophosphate, or a combination thereof

19. The method of Clause 13 wherein the biopolymer includes chitosan, ananalog of chitosan, or a combination thereof.

20. The method of Clause 19 wherein the chemical crosslinking agentincludes genipin, a derivative of genipin, an analog of genipin, or acombination thereof.

21. The method of Clause 20 wherein a weight ratio of the biopolymer tothe chemical crosslinking agent within the tissue scaffold material iswithin a range from 10:1 to 100:1.

22. A system for treating an aneurysm, the system comprising:

-   -   a first precursor material including a biopolymer;    -   a second precursor material including a chemical crosslinking        agent; and    -   a catheter including an elongate lumen and an exit port at a        distal end portion of the lumen, wherein the catheter is        configured to convey a mixture of the first and second precursor        materials toward and into an internal volume of an aneurysm at a        portion of a blood vessel via the lumen and via the exit port,        and wherein the catheter is at most 3 French.

23. The system of Clause 22, wherein the biopolymer has a non-zerodegree of chemical crosslinking within the first precursor material.

24. The system of Clause 22 wherein:

-   -   (a) the first precursor material includes a physical        crosslinking agent;    -   (b) the second precursor material includes a physical        crosslinking agent;    -   (c) the system further comprises a third precursor material        including a physical crosslinking agent; or    -   (d) any combination of (a), (b) and (c).

25. The system of Clause 24 wherein:

-   -   the biopolymer includes chitosan, a derivative of chitosan, an        analog of chitosan, or a combination thereof;    -   the chemical crosslinking agent includes genipin, a derivative        of genipin, an analog of genipin, or a combination thereof; and    -   the physical crosslinking agent includes β-glycerophosphate, a        derivative of β-glycerophosphate, an analog of        β-glycerophosphate, or a combination thereof

26. The system of Clause 22 wherein the biopolymer includes chitosan, aderivative of chitosan, an analog of chitosan, or a combination thereof.

27. The system of Clause 26 wherein the chemical crosslinking agentincludes genipin, a derivative of genipin, an analog of genipin, or acombination thereof.

28. The system of Clause 22 wherein:

-   -   (a) the first precursor material includes a contrast agent;    -   (b) the second precursor material includes a contrast agent;    -   (c) the system further comprises a third precursor material        including a contrast agent; or    -   (d) any combination of (a), (b) and (c).

29. The system of Clause 28 wherein the contrast agent is selected toprovide diminishing radiopacity.

30. The system of Clause 28 wherein the contrast agent includes iohexol,a derivative of iohexol, an analog of iohexol, or a combination thereof.

31. A method for at least partially filling a volume at a treatmentlocation, the method comprising:

-   -   advancing a catheter toward the treatment location, wherein the        catheter includes an elongate lumen and an exit port at a distal        end portion of the lumen;    -   mixing a biopolymer and a chemical crosslinking agent to        initiate chemical crosslinking of the biopolymer;    -   flowing the biopolymer and the chemical crosslinking agent        toward the volume via the lumen while the chemical crosslinking        is ongoing; and    -   delivering the biopolymer and the chemical crosslinking agent        from the lumen into the volume via the exit port while the        chemical crosslinking is ongoing.

32. The method of Clause 31, wherein advancing the catheter comprisesadvancing the catheter through a blood vessel.

33. The method of Clause 31, wherein the treatment location comprises ananeurysm and the volume comprises an internal volume of the aneurysm.

34. The method of Clause 31, wherein the treatment location comprises avein and the volume comprises a lumen of the vein.

35. The method of Clause 34, wherein the vein is located in a leg.

36. The method of Clause 35, further comprising reducing leg veinvaricosity by occluding the vein lumen via said delivering.

37. The method of Clause 31, wherein the treatment location comprises anartery that vascularizes a tumor and the volume comprises a lumen of theartery.

38. The method of Clause 31, wherein the treatment location comprises avascular or cardiovascular implant and the volume comprises an endoleak.

39. The method of Clause 31 wherein:

-   -   the biopolymer has a non-zero degree of chemical crosslinking        before being mixed with the chemical crosslinking agent; and    -   mixing the biopolymer and the chemical crosslinking agent        includes mixing the biopolymer and the chemical crosslinking        agent to increase the degree of chemical crosslinking.

40. The method of Clause 31 wherein delivering the biopolymer and thechemical crosslinking agent from the lumen into the volume includesdelivering the biopolymer and the chemical crosslinking agent from thelumen into the volume as components of a single cohesive strand that atleast partially agglomerates to form a mass occupying at least 75% ofthe volume, and wherein the volume is a total internal volume of ananeurysm.

41. The method of Clause 31, further comprising:

-   -   flowing a physical crosslinking agent toward the volume via the        lumen with the biopolymer and the chemical crosslinking agent;        and    -   delivering the physical crosslinking agent from the lumen into        the volume via the exit port with the biopolymer and the        chemical crosslinking agent.

42. The method of Clause 41 wherein:

-   -   the biopolymer includes chitosan, a derivative of chitosan, an        analog of chitosan, or a combination thereof;    -   the chemical crosslinking agent includes genipin, a derivative        of genipin, an analog of genipin, or a combination thereof; and    -   the physical crosslinking agent includes β-glycerophosphate, a        derivative of β-glycerophosphate, an analog of        β-glycerophosphate, or a combination thereof

43. The method of Clause 31 wherein the biopolymer includes chitosan, aderivative of chitosan, an analog of chitosan, or a combination thereof.

44. The method of Clause 43 wherein the chemical crosslinking agentincludes genipin, a derivative of genipin, an analog of genipin, or acombination thereof.

45. The method of Clause 44 wherein mixing the biopolymer and thechemical crosslinking agent includes mixing the biopolymer and thechemical crosslinking agent such that a weight ratio of the biopolymerto the chemical crosslinking agent is within a range from 10:1 to 100:1.

46. The method of Clause 31, wherein the treatment location comprises ananeurysm and the volume comprises an internal volume of the aneurysm,and further comprising reinforcing a neck of the aneurysm while thebiopolymer and the chemical crosslinking agent are disposed within theinternal volume and while the chemical crosslinking is ongoing.

47. The method of Clause 46, further comprising:

-   -   intravascularly advancing a balloon toward a portion of a blood        vessel near the aneurysm while the balloon is in a low-profile        state; and    -   moving the balloon from the low-profile state toward an expanded        state after advancing the balloon toward the portion of the        blood vessel,    -   wherein reinforcing the neck includes reinforcing the neck with        the balloon in the expanded state.

48. The method of Clause 47, further comprising:

-   -   intravascularly advancing a tubular flow diverter toward the        portion of the blood vessel while the flow diverter is in a        low-profile state; and    -   moving the flow diverter from the low-profile state toward an        expanded state after advancing the flow diverter toward the        portion of the blood vessel,    -   wherein reinforcing the neck includes reinforcing the neck with        the flow diverter in the expanded state.

BRIEF DESCRIPTION OF THE DRAWINGS

Many aspects of the present technology can be better understood withreference to the following drawings. The components in the drawings arenot necessarily to scale. Instead, emphasis is placed on illustratingclearly the principles of the present technology. For ease of reference,throughout this disclosure identical reference numbers may be used toidentify identical, similar, or analogous components or features of morethan one embodiment of the present technology.

FIG. 1 is a top plan view of a system for treating intracranialaneurysms in accordance with an embodiment of the present technology.

FIG. 2 is a flow chart illustrating a method for treating anintracranial aneurysm in accordance with an embodiment of the presenttechnology.

FIGS. 3-12 are anatomical side views of portions of the system shown inFIG. 1 within an intracranial blood vessel at different respectivestages during the method shown in FIG. 2 .

FIG. 13 is a plot of storage modulus (measured by rheometer) and lossmodulus (also measured by rheometer) relative to time for a tissuescaffold material in accordance with an embodiment of the presenttechnology.

FIGS. 14 and 15 are plots, respectively, of storage modulus (measured bydynamic mechanical analysis) and loss modulus (also measured by dynamicmechanical analysis) relative to time for the tissue scaffold materialof FIG. 13 .

DETAILED DESCRIPTION

Systems, devices, and methods in accordance with embodiments of thepresent technology can at least partially address one or more problemsassociated with conventional technologies whether or not such problemsare stated herein. Methods for treating intracranial aneurysms inaccordance with at least some embodiments of the present technologyinclude introducing an injectable scaffold material into the internalvolume of an intracranial aneurysm (aneurysm internal volume). In animalstudies, such methods have been found to provide (a) complete or nearlycomplete volumetric filling of the aneurysm internal volume, and (b)complete or nearly complete coverage of the aneurysm neck with newendothelial tissue. These features, among others, are expected to resultin a lower recanalization rate than that of platinum coil treatments andfaster aneurysm occlusion than that of flow diverters. Furthermore, theinjectable scaffold material is expected to be bioabsorbed and therebyreduced in volume over time. Thus, unlike platinum coils, the injectablescaffold is expected to have little or no long-term mass effect.Furthermore, the injectable scaffold material can be configured to havediminishing radiopacity; therefore, when so configured it will notinterfere future CT and MRI imaging and procedures. Embodiments of thepresent technology can have these and/or other features and advantagesrelative to conventional counterparts whether or not such features andadvantages are described herein.

Specific details of systems, devices, and methods for treatingintracranial aneurysms in accordance with embodiments of the presenttechnology are described herein with reference to FIGS. 1-15 . Althoughthese systems, devices, and methods may be described herein primarily orentirely in the context of treating saccular intracranial aneurysms,other contexts are within the scope of the present technology. Forexample, suitable features of described systems, devices, and methodsfor treating saccular intracranial aneurysms can be implemented in thecontext of treating non-saccular intracranial aneurysms, abdominalaortic aneurysms, thoracic aortic aneurysms, renal artery aneurysms,arteriovenous malformations, tumors (e.g. via occlusion of vessel(s)feeding a tumor), perivascular leaks, varicose veins (e.g. via occlusionof one or more truncal veins such as the great saphenous vein),hemorrhoids, and sealing endoleaks adjacent to artificial heart valves,covered stents, and abdominal aortic aneurysm devices among otherexamples. Furthermore, it should understood, in general, that othersystems, devices, and methods in addition to those disclosed herein arewithin the scope of the present disclosure. For example, systems,devices, and methods in accordance with embodiments of the presenttechnology can have different and/or additional configurations,components, procedures, etc. than those disclosed herein. Moreover,systems, devices, and methods in accordance with embodiments of thepresent disclosure can be without one or more of the configurations,components, procedures, etc. disclosed herein without deviating from thepresent technology.

FIG. 1 is a top plan view of a system 100 for treating intracranialaneurysms in accordance with an embodiment of the present technology.The system 100 can include a first container 102 containing a firstprecursor material 103 (shown schematically), a second container 104containing a second precursor material 105 (also shown schematically),and a mixing device 106 suitable for mixing the first and secondprecursor materials 103, 105. The mixing device 106 can include mixingsyringes 108 (individually identified as mixing syringes 108 a, 108 b)and a coupler 110 extending between respective exit ports (not shown) ofthe mixing syringes 108. The mixing syringes 108a, 108b each include aplunger 112 and a barrel 114 in which the plunger 112 is slidablyreceived.

The system 100 can further include an injection syringe 116 and a firstcatheter 118 configured to deliver and receive, respectively, a mixtureof the first and second precursor materials 103, 105 from the injectionsyringe 116. The injection syringe 116 can include a barrel 120, an exitport 122 at one end of the barrel 120, and a plunger 124 slidablyreceived within the barrel 120 via an opposite end of the barrel 120.The first catheter 118 can include an elongate shaft 126 defining anelongate lumen (not shown), an exit port 128 at a distal end portion ofthe lumen, and a coupler 130 at a proximal end portion of the lumen. Thecoupler 130 can be configured to form a secure fluidic connectionbetween the lumen and the exit port 122 of the injection syringe 116.The first catheter 118 can be configured to receive a mixture of thefirst and second precursor materials 103, 105 from the injection syringe116 via the coupler 130 and to convey the mixture toward and into theinternal volume of an intracranial aneurysm (or other treatment locationsuch as any of those described herein) via the lumen and via the exitport 128. The system 100 can further include a second catheter 132including an elongate sheath 134 and a wire 136 slidably disposed withinthe sheath 134. At a distal end portion of the wire 136, the secondcatheter 132 can include an atraumatic hook 138. The first and secondcatheters 118, 132 can be steerable or non-steerable and can beconfigured for deployment by guide wire, by guide sheath, or in anothersuitable manner. Furthermore, the first and second catheters 118, 132can be of suitable sizes to both be located within an intracranial bloodvessel at the same time. In at least some cases, the first catheter 118is at most 3 French and/or the second catheter 132 is at most 3 French.

The system 100 can also include a tubular stent such as a flow diverter140 carried by the second catheter 132 proximal to the hook 138. Theflow diverter 140 can have an expanded state (as shown) and alow-profile state (e.g., a collapsed state) in which the flow diverter140 is sufficiently compact to move longitudinally within the sheath134. In at least some cases, the flow diverter 140 includes filamentsthat shift relative to one another as the flow diverter 140 movesbetween its expanded and low-profile states. The flow diverter 140, forexample, can be a braided tube.

FIG. 2 is a flow chart illustrating a method 200 for treating anintracranial aneurysm in accordance with an embodiment of the presenttechnology, and FIGS. 3-12 are anatomical side views of portions of thesystem 100 within an intracranial blood vessel 300 at differentrespective stages during the method 200. With reference first to FIGS. 2and 3 together, the method 200 can include intravascularly advancing thefirst catheter 118 toward an intracranial aneurysm 302 (or othertreatment location such as any of those described herein) along theblood vessel 300 (block 202). The method 200 can further includeextending the shaft 126 though a neck 304 of the aneurysm 302 to locatethe exit port 128 within an internal volume of the aneurysm 302 (block204). Portions of the first catheter 118 around the exit port 128 can beatraumatic to avoid damaging the aneurysm 302 during positioning of theexit port 128. Although the internal volume of the aneurysm 302 is emptyof non-anatomical material or structures in the illustrated embodiment,in other embodiments, the internal volume of the aneurysm 302 maycontain such material or structures. For example, the internal volume ofthe aneurysm 302 may contain a previously introduced embolization coilor mesh. Therefore, the various embodiments of the method 200 canfurther comprise introduction of a permanent intrasaccular device suchas an embolization coil or mesh embolization device (e.g. a mesh coilhaving a series of expanding petals such as the MEDINA™ EmbolizationDevice from Medtronic). Such embodiments of the method can compriseintroducing one or more such permanent intrasaccular devices into theaneurysm before delivering the scaffold material into the aneurysm.

With reference now to FIGS. 1, 2 and 4 together, the method 200 canfurther include advancing the second catheter 132 toward the aneurysm302 (block 206) while the flow diverter 140 (FIG. 1 ) is in itslow-profile state. Next, with reference to FIGS. 1, 2 and 5 together,the method 200 can include reinforcing the neck 304 (block 208) bymoving the flow diverter 140 from its low-profile state toward itsexpanded state within a main lumen 306 of the blood vessel 300. Inaddition to reinforcing the neck 304, the flow diverter 140 canstabilize the position of the exit port 128 within the aneurysm 302 bypressing a portion of the shaft 126 against a wall 308 of the bloodvessel 300. In an alternative embodiment, the flow diverter 140 isreplaced with a balloon configured to be intravascularly advanced in alow-profile state (e.g., a deflated state) and deployed in an expandedstate (e.g., an at least partially inflated state). Use of a balloon inplace of a flow diverter may be advantageous, for example, when theintravascular anatomy around an aneurysm is not suitable for deploying aflow diverter. In some cases, a balloon that replaces the flow diverter140 is a tubular balloon having an annular form or another suitable formwith a longitudinal flow passage therethrough for avoiding complete ornear complete occlusion of a blood vessel in which the balloon isdeployed. Alternatively, a balloon that lacks such a flow passage may beused when such complete or near complete occlusion of a blood vessel isacceptable.

With reference to FIGS. 1, 2 and 6 together, the method 200 can includemixing the first and second precursor materials 103, 105 (block 210) toform a tissue scaffold material 310. In a particular example, the firstprecursor material 103 is loaded into one of the barrels 114, the secondprecursor materials 105 is loaded into the other barrel 114, and themixing syringes 108 are coupled via the coupler 110. To mix the firstand second precursor materials 103, 105, the plungers 112 arealternately depressed, thereby causing the first and second precursormaterials 103, 105 to move repeatedly from one barrel 114 to the otherbarrel 114. After suitably mixing the precursor materials, the resultingtissue scaffold material 310 can be loaded into the barrel 120 of theinjection syringe 116. When the lumen within the first catheter 118 isvery narrow (e.g., when the first catheter 118 is at most 3 French), aconsiderable amount of pressure may be necessary to move the tissuescaffold material 310 through the lumen to the aneurysm 302.Accordingly, the injection syringe 116 is configured to withstand highpressure, such as at least 500 psi.

The first and second precursor materials 103, 105 (FIG. 1 ) can includea biopolymer and a chemical crosslinking agent, respectively. Thechemical crosslinking agent can be selected to form covalent crosslinksbetween chains of the biopolymer. In some embodiments, the biopolymer ofthe first precursor material 103 includes chitosan or a derivative oranalog thereof, and the chemical crosslinking agent of the secondprecursor material 105 includes genipin or a derivative or analogthereof. Other suitable crosslinking agents for use with chitosaninclude glutaraldehyde, functionalized polyethylene glycol, andderivatives and analogs thereof. In other embodiments, the biopolymer ofthe first precursor material 103 can include collagen or a derivative oranalog thereof, and the chemical crosslinking agent of the secondprecursor material 105 can include hexamethylene diisocyanate or aderivative or analog thereof Alternatively or in addition, genipin or aderivative or analog thereof can be used as a chemical crosslinkingagent for a collagen-based biopolymer. In still other embodiments, thebiopolymer of the first precursor material 103 and the chemicalcrosslinking agent of the second precursor material 105 can includeother suitable compounds alone or in combination.

Mixing the biopolymer of the first precursor material 103 and thechemical crosslinking agent of the second precursor material 105 caninitiate chemical crosslinking of the biopolymer. After the first andsecond precursor materials 103, 105 are mixed, chemical crosslinking ofthe biopolymer occurs for enough time to allow the resulting tissuescaffold material 310 to be delivered to the aneurysm 302 beforebecoming too viscous to move through the lumen of the first catheter118. In addition, the period of time during which chemical crosslinkingof the biopolymer occurs can be short enough to reach a target deployedviscosity within a reasonable time (e.g., in the range of 10-60 minutes;or at most 40 minutes, 30 minutes, 20 minutes, or 10 minutes) afterdelivery. The target deployed viscosity can be high enough to cause anagglomeration of the tissue scaffold material 310 to remain within theinternal volume of the aneurysm 302 without reinforcing the neck 304.

In at least some cases, the biopolymer has a non-zero degree of chemicalcrosslinking within the first precursor material 103 before mixing withthe chemical crosslinking agent. This can be useful, for example, tocustomize the curing window for the tissue scaffold material 310 so thatit corresponds well with an expected amount of time needed to deliverthe material to the aneurysm 302. The degree of chemical crosslinking ofthe biopolymer within the first precursor material 103 before mixingwith the chemical crosslinking agent, the ratio of the biopolymer to thechemical crosslinking agent, and/or one or more other variables can beselected to cause the tissue scaffold material 310 to have a viscositysuitable for delivery to the aneurysm 302 via the lumen of the firstcatheter 118 for a suitable period of time (e.g., a period within arange from 10 minutes to 40 minutes) after mixing of the first andsecond precursor materials 103, 105. In at least some cases, the firstand second precursor materials 103, 105 are mixed in proportions thatcause a weight ratio of the biopolymer to the chemical crosslinkingagent in the resulting tissue scaffold material 310 to be within a rangefrom 10:1 to 100:1, such as from 10:1 to 30:1, or from 15:1 to 50:1, orfrom 15:1 to 25:1. In a particular example, the first and secondprecursor materials 103, 105 are mixed in proportions that cause aweight ratio of the biopolymer to the chemical crosslinking agent in theresulting tissue scaffold material 310 to be 30:1.

Use of a biopolymer instead of an artificial polymer in the firstprecursor material 103 may be advantageous because biopolymers tend tobe more readily bioabsorbed than artificial polymers and/or for otherreasons. Furthermore, use of a chemical crosslinking agent instead of aphysical crosslinking agent (i.e., a crosslinking agent that formsnoncovalent crosslinks between chains of the biopolymer) in the secondprecursor material 105 may be advantageous because chemicallycrosslinked polymers tend to be more cohesive than physicallycrosslinked polymers and/or for other reasons. In the context of forminga tissue scaffold within an aneurysm, high cohesiveness of the tissuescaffold material 310 may be more important than it is in other contextsto secure the cured tissue scaffold material 310 within the aneurysm302. For example, high cohesiveness of the tissue scaffold material 310may reduce or eliminate the possibility of a piece of the tissuescaffold material 310 breaking free and entering a patient'sintracerebral blood stream during delivery.

The first and second precursor materials 103, 105 may include othercomponents and/or the system 100 may include other precursor materialsintended for mixing with the first and second precursor materials 103,105. For example, the first, second, and/or another precursor materialmay include a physical crosslinking agent. The presence of a physicalcrosslinking agent may be useful to form physical crosslinks thatcomplement chemical crosslinks from the chemical crosslinking agent. Thecombination of chemical and physical crosslinks may enhance thecohesiveness of the tissue scaffold material 310. Suitable physicalcrosslinking agents for use with chitosan-based biopolymers include βglycerophosphate, mannitol, glucose, and derivatives and analogsthereof. In these and other cases, the tissue scaffold material 310 mayinclude multiple chemical crosslinking agents and/or multiple physicalcrosslinking agents.

A contrast agent is another component that may be added to the precursormaterials. The presence of a contrast agent within the tissue scaffoldmaterial 310 can be useful to visualize delivery of the tissue scaffoldmaterial 310 using fluoroscopy. One problem with using conventionalplatinum coils in intracranial aneurysms is that the persistentradiopacity of the coils tends to interfere with visualizing otheraspects of the treatment in follow-up imaging. For example, the presenceof platinum coils within an aneurysm may make it difficult or impossibleto detect by fluoroscopy the presence of blood-carried contrast agentthat would otherwise indicate recanalization. In at least someembodiments of the present technology, a contrast agent within thetissue scaffold material 310 is selected to provide radiopacity thatdiminishes over time. For example, the contrast agent may initially beradiopaque to facilitate delivery of the tissue scaffold material 310and then become less radiopaque to facilitate follow-up imaging. In aparticular example, the first, second, and/or another precursor materialincludes iohexol or a derivative or analog thereof as a suitablecontrast agent.

With reference again to FIGS. 1, 2 and 6 together, the method 200 caninclude delivering the tissue scaffold material 310 into an internalvolume of the aneurysm 302 (block 212). For example, the method 200 caninclude delivering the tissue scaffold material 310 through the lumen ofthe first catheter 118 so that the tissue scaffold material 310 flowsthrough the exit port 128 of the first catheter 118 and into theaneurysm 302. As the tissue scaffold material 310 passes through thelumen of the first catheter 118, chemical crosslinking of the biopolymercan continue to occur. As shown in FIG. 6 , the tissue scaffold material310 can exit the exit port 128 of the first catheter 118 as a singlecohesive strand 312. As shown in FIG. 7 , as more tissue scaffoldmaterial 310 is delivered to the aneurysm 302, the strand 312 can atleast partially agglomerate to form a mass 314. In the illustratedembodiment, the mass 314 occupies all of the internal volume of theaneurysm 302 and the area of the aneurysm neck 304. In otherembodiments, the mass 314 can occupy less than all (e.g., from 20% to100%, from 50% to 100%, or from 75% to 100%) of the total internalvolume of the aneurysm 302, particularly but not exclusively when usedin combination with additional aneurysm treatments such as embolic coilsor implants.

With reference to FIGS. 1, 2 and 8 , the method 200 can include removingthe first catheter 118 (block 214) after forming the mass 314. Themethod 200 can further include reinforcing the neck 304 while the tissuescaffold material 310 is disposed within the internal volume of theaneurysm 302 and while chemical crosslinking of the biopolymer continuesto occur. The neck 304 can be obstructed by the combination of the mass314 and the flow diverter 140 (or balloon or other luminal intraluminaldevice(s)) holding the mass 314 in place until sufficient chemicalcrosslinking of the biopolymer has occurred.

With reference to FIGS. 1, 2 and 9 , the method 200 can also includereducing or removing reinforcement of the neck 304 (block 216). Forexample, the flow diverter 140 can be moved from its expanded statetoward its low-profile state and simultaneously or subsequentlyretracted into the sheath 134. After the tissue scaffold material 310 isdisposed within the internal volume of the aneurysm 302 and before thereinforcement of the neck 304 is reduced or removed, the number ofchemical crosslinks within the tissue scaffold material 310 may increaseby at least 5%, at least 10%, or at least 15%. In at least some cases,the tissue scaffold material 310 has a first storage modulus on a pascalscale immediately after being disposed within the internal volume of theaneurysm 302, a second storage modulus on a pascal scale immediatelyafter reinforcement of the neck 304 is reduced, and a third storagemodulus on a pascal scale at an endpoint of the chemical crosslinking.The second storage modulus can be at least 20% greater than the firststorage modulus. Furthermore, the first storage modulus can be within arange from 40% to 80% of the third storage modulus.

After the flow diverter 140 has been stowed within the sheath 134, themethod 200 can include removing the second catheter 132 (block 218). Asshown in FIG. 10 , the mass 314 can remain securely lodged within theinternal volume of the aneurysm 302 after the second catheter 132 isremoved. Over time, as shown in FIG. 11 , natural vascular remodelingmechanisms and/or bioabsorption of the mass 314 may lead to formation ofa thrombus 316 and/or conversion of entrapped thrombus 316 to fibroustissue within the internal volume of the aneurysm 302. These mechanismsalso may lead to cell death at a wall 318 of the aneurysm 302 and growthof new endothelial cells 320 along a surface of the thrombus 316bordering the main lumen 306 of the blood vessel 300. Eventually, thethrombus 316 and the cells at the wall 318 of the aneurysm 302 may fullydegrade, leaving behind a successfully remodeled region of the bloodvessel 300 (FIG. 12 ). In should be noted that, although the flowdiverter 140 is removed in the illustrated embodiment, in otherembodiment, the flow diverter 140 can be left in place. In theseembodiments, the new endothelial cells 320 can grow between and overfilaments or struts of the flow diverter 140.

EXAMPLES

The following examples are provided to illustrate certain particularembodiments of the disclosure. It should be understood that additionalembodiments not limited to the particular features described areconsistent with the following examples.

Example 1 Tissue Scaffold Material

A tissue scaffold material was prepared as a solution of 3.8% chitosan,2.9% β glycerophosphate, and 0.1% genipin (all percentagesweight/volume). The ratio of genipin to chitosan in the resulting tissuescaffold material was 38:1. FIG. 13 is a plot of storage modulus andloss modulus relative to time for the tissue scaffold material. Thevalues in FIG. 13 were measured by rheometer beginning 2 minutes aftermixing the solutions. Similarly, FIGS. 14 and 15 are plots,respectively, of storage modulus and loss modulus relative to time forthe tissue scaffold material. The values in FIGS. 14 and 15 weremeasured by dynamic mechanical analysis beginning 30 minutes aftermixing the solutions. Tissue scaffold materials in accordance with someembodiments of the present technology have storage modulus and/or lossmodulus values at a given time after mixing within 25% (e.g., within10%) of the corresponding values shown in FIGS. 13-15 . Tissue scaffoldmaterials in accordance with other embodiments of the present technologycan have other suitable storage modulus and loss modulus values.

Example 2 Bench Test

A flow loop with a model aneurysm (10 mm pouch diameter; 4 mm neckdiameter) was used for bench testing the tissue scaffold material(Example 1). The distal end of a MARKSMAN® (ID 0.027″) microcatheter waslocated within the model aneurysm and secured by deploying a PIPELINEFLEX™ Embolization Device (Medtronic) (“P-Flex device”) across the neckof the model aneurysm. The tissue scaffold material was injected intothe model aneurysm via the microcatheter within 10 minutes of mixing thechitosan, β glycerophosphate, and genipin solutions. The resulting massof tissue scaffold material was found to be stable within the modelaneurysm for 2 hours under simulated pulsatile blood flow of 600 mL perminute.

Example 3 Animal Test (9-Day Follow Up)

Two model aneurysms (distal and proximal) were created in the carotidartery of each of two canine subjects. The model aneurysms had pouchdiameters of approximately 10 mm and neck diameters of approximately 4mm. Tissue scaffold material (Example 1) was injected into the distaland proximal model aneurysms of the first subject and into the distalmodel aneurysm of the second subject via the microcatheter (Example 2).P-Flex devices were deployed across the neck of the proximal modelaneurysm of the first subject and across the necks of the distal andproximal model aneurysms of the second subject. After 9 days, thesubject animals were euthanized and the model aneurysms were biopsied.The biopsies showed that the model aneurysms having the tissue scaffoldmaterial and a P-Flex device contained well-developed aneurismal thrombiencompassing all or nearly all of the model aneurysms' internal volumes.The model aneurysm having the tissue scaffold material and not having aP-Flex device included an aneurismal thrombus encompassing most of themodel aneurysm's internal volume, but with some vacant areas at theperimeter of the internal volume near the model aneurysm's neck. Themodel aneurysm having a P-Flex device and not having the tissue scaffoldmaterial did not contain an aneurismal thrombus. No inflammation wasobserved in the parent vessels.

Example 4 Animal Test (90-Day Follow Up)

Two model aneurysms (distal and proximal) were created in the carotidartery of each of two canine subjects. The model aneurysms had pouchdiameters of approximately 10 mm and neck diameters of approximately 4mm. Tissue scaffold material (Example 1) was injected into the distalmodel aneurysm of the first subject and into the distal and proximalmodel aneurysms of the second subject via the microcatheter (Example 2).Platinum coils were introduced into the proximal model aneurysm of thefirst subject. A P-Flex device and a SOLITAIRE® Stent were deployed,respectively, across the necks of the distal and proximal modelaneurysms of the first subject. After 90 days, the subject animals wereeuthanized and the model aneurysms were biopsied. The biopsies showedthat the model aneurysms having the tissue scaffold material and nothaving a P-Flex device or a SOLITAIRE° stent as well as the modelaneurysm having the tissue scaffold material and the P-Flex deviceshowed complete endothelial coverage at the aneurismal neck.

Conclusion

This disclosure is not intended to be exhaustive or to limit the presenttechnology to the precise forms disclosed herein. Although specificembodiments are disclosed herein for illustrative purposes, variousequivalent modifications are possible without deviating from the presenttechnology, as those of ordinary skill in the relevant art willrecognize. In some cases, well-known structures and functions have notbeen shown and/or described in detail to avoid unnecessarily obscuringthe description of the embodiments of the present technology. Althoughsteps of methods may be presented herein in a particular order, inalternative embodiments the steps may have another suitable order.Similarly, certain aspects of the present technology disclosed in thecontext of particular embodiments can be combined or eliminated in otherembodiments. Furthermore, while advantages associated with certainembodiments may have been disclosed in the context of those embodiments,other embodiments may also exhibit such advantages, and not allembodiments need necessarily exhibit such advantages or other advantagesdisclosed herein to fall within the scope of the present technology.

Throughout this disclosure, the singular terms “a,” “an,” and “the”include plural referents unless the context clearly indicates otherwise.Similarly, unless the word “or” is expressly limited to mean only asingle item exclusive from the other items in reference to a list of twoor more items, then the use of “or” in such a list is to be interpretedas including (a) any single item in the list, (b) all of the items inthe list, or (c) any combination of the items in the list. Additionally,the terms “comprising” and the like may be used herein to mean includingat least the recited feature(s) such that any greater number of the samefeature(s) and/or one or more additional types of features are notprecluded. Directional terms, such as “upper,” “lower,” “front,” “back,”“vertical,” and “horizontal,” may be used herein to express and clarifythe relationship between various elements. It should be understood thatsuch terms do not denote absolute orientation. Reference herein to “oneembodiment,” “an embodiment,” or similar formulations means that aparticular feature, structure, operation, or characteristic described inconnection with the embodiment can be included in at least oneembodiment of the present technology. Thus, the appearances of suchphrases or formulations herein are not necessarily all referring to thesame embodiment. Furthermore, various particular features, structures,operations, or characteristics may be combined in any suitable manner inone or more embodiments of the present technology.

We claim:
 1. A method for treating an aneurysm, the method comprising:intravascularly advancing a catheter toward an aneurysm at a portion ofa blood vessel, wherein the catheter includes an elongate lumen and anexit port at a distal end portion of the elongate lumen; mixing abiopolymer and a chemical crosslinking agent to initiate chemicalcrosslinking of the biopolymer; flowing the biopolymer and the chemicalcrosslinking agent toward an internal volume of the aneurysm via theelongate lumen while the chemical crosslinking is ongoing; anddelivering the biopolymer and the chemical crosslinking agent from theelongate lumen into the internal volume via the exit port while thechemical crosslinking is ongoing.
 2. The method of claim 1 wherein theaneurysm is an intracranial aneurysm.
 3. The method of claim 1 wherein:the biopolymer has a non-zero degree of chemical crosslinking beforebeing mixed with the chemical crosslinking agent; and mixing thebiopolymer and the chemical crosslinking agent includes mixing thebiopolymer and the chemical crosslinking agent to increase the degree ofchemical crosslinking.
 4. The method of claim 1 wherein delivering thebiopolymer and the chemical crosslinking agent from the elongate lumeninto the internal volume includes delivering the biopolymer and thechemical crosslinking agent from the elongate lumen into the internalvolume as components of a single cohesive strand that at least partiallyagglomerates to form a mass occupying at least 75% of the internalvolume, and wherein the internal volume is a total internal volume ofthe aneurysm.
 5. The method of claim 1, further comprising: flowing aphysical crosslinking agent toward the internal volume via the elongatelumen with the biopolymer and the chemical crosslinking agent; anddelivering the physical crosslinking agent from the elongate lumen intothe internal volume via the exit port with the biopolymer and thechemical crosslinking agent.
 6. The method of claim 5 wherein: thebiopolymer includes chitosan, a derivative of chitosan, an analog ofchitosan, or a combination thereof; the chemical crosslinking agentincludes genipin, a derivative of genipin, an analog of genipin, or acombination thereof; and the physical crosslinking agent includesβ-glycerophosphate, a derivative of β-glycerophosphate, an analog ofβ-glycerophosphate, or a combination thereof.
 7. The method of claim 1wherein the biopolymer includes chitosan, a derivative of chitosan, ananalog of chitosan, or a combination thereof.
 8. The method of claim 7wherein the chemical crosslinking agent includes genipin, a derivativeof genipin, an analog of genipin, or a combination thereof.
 9. Themethod of claim 8 wherein mixing the biopolymer and the chemicalcrosslinking agent includes mixing the biopolymer and the chemicalcrosslinking agent such that a weight ratio of the biopolymer to thechemical crosslinking agent is within a range from 10:1 to 100:1. 10.The method of claim 1, further comprising reinforcing a neck of theaneurysm while the biopolymer and the chemical crosslinking agent aredisposed within the internal volume and while the chemical crosslinkingis ongoing.
 11. The method of claim 10, further comprising:intravascularly advancing a balloon toward the portion of the bloodvessel while the balloon is in a low-profile state; and moving theballoon from the low-profile state toward an expanded state afteradvancing the balloon toward the portion of the blood vessel, whereinreinforcing the neck includes reinforcing the neck with the balloon inthe expanded state.
 12. The method of claim 10, further comprising:intravascularly advancing a tubular flow diverter toward the portion ofthe blood vessel while the flow diverter is in a low-profile state; andmoving the flow diverter from the low-profile state toward an expandedstate after advancing the flow diverter toward the portion of the bloodvessel, wherein reinforcing the neck includes reinforcing the neck withthe flow diverter in the expanded state.
 13. A method for treating ananeurysm, the method comprising: intravascularly advancing a cathetertoward an aneurysm at a portion of a blood vessel, wherein the catheterincludes an elongate lumen and an exit port at a distal end portion ofthe elongate lumen; injecting a mixture of a biopolymer and a chemicalcrosslinking agent into the elongate lumen using a syringe, wherein thesyringe is configured to withstand a pressure of at least 500 psi;flowing the mixture of the biopolymer and the chemical crosslinkingagent toward an internal volume of the aneurysm via the lumen; anddelivering the mixture of the biopolymer and the chemical crosslinkingagent from the lumen into the internal volume via the exit port, whereinthe mixture is delivered as a cohesive strand from the exit port, andthe cohesive strand at least partially agglomerates to form a masswithin the internal volume.
 14. The method of claim 13 wherein themixture further comprises a physical crosslinking agent.
 15. The methodof claim 14 wherein: the biopolymer includes chitosan, a derivative ofchitosan, an analog of chitosan, or a combination thereof; the chemicalcrosslinking agent includes genipin, a derivative of genipin, an analogof genipin, or a combination thereof; and the physical crosslinkingagent includes β-glycerophosphate, a derivative of β-glycerophosphate,an analog of β-glycerophosphate, or a combination thereof.
 16. Themethod of claim 13 wherein the mixture further comprises a contrastagent.
 17. The method of claim 13, further comprising: loading themixture into the syringe; and coupling the syringe to the elongate lumenof the catheter.
 18. The method of claim 13, further comprisingimplanting an intrasaccular device within the internal volume before themixture is delivered into the internal volume.
 19. The method of claim13, wherein the elongate lumen has a size of at most 3 French.
 20. Themethod of claim 13, further comprising reinforcing a neck of theaneurysm while delivering the mixture of the biopolymer and the chemicalcrosslinking agent from the lumen into the internal volume.